Triple negative (estrogen receptor, progesterone receptor, HER2-neu negative) breast cancers (TNBC) account for 15% of all breast cancers but are responsible for a disproportionate number of deaths and are significantly associated with race. Overexpression of the histone methyltransferase Enhancer of Zeste Homologue 2 (EZH2) is an independent prognostic biomarker significantly associated with poorly-differentiated TNBCs and poor patient outcome. It is our overall hypothesis that EZH2 has non-canonical functions in the setting of TNBC. We further hypothesize that concordant expression of EZH2 and non-canonical substrates may identify novel biomarkers of aggressive and metastatic disease. In order to test this hypothesis, we propose two aims. In our first aim, we will determine the contribution of non-canonical EZH2 function to TNBC progression and metastasis. Based on our preliminary studies, we have identified the oncoprotein p38 MAPK as a novel substrate of EZH2. We will use site-directed to determine the effects of EZH2-mediated methylation of p38 on TNBC progression and metastatic phenotypes in vitro and in vivo. In our second aim, we will determine the prognostic relevance of concordant cytoplasmic EZH2 and activated p38 expression in well- annotated cohorts of human tissue samples. Based on our preliminary data, we hypothesize that this concordant expression may identify a subset of aggressive TNBCs that may be associated with race. Taken together, this study will investigate the molecular mechanisms that underlie aggressive TNBC phenotypes, with direct applications in prognostication.